Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray

Disclosures

Kidney Int. 2011;80(11):1122-1137. 

In This Article

Abstract and Introduction

Abstract

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patient's kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Introduction

In May 2010, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference titled 'Drug Prescribing in Kidney Disease: Initiative for Improved Dosing'. The conference, attended by 50 international experts, including representatives from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), was designed to explore our understanding of drug disposition in patients with acute kidney injury (AKI) and chronic kidney disease (CKD), and to propose recommendations for the optimization of pharmacotherapy in the most common clinical practice settings. The plenary session presentations were followed by breakout group discussions to address four specific issues that the conference planning committee considered to be of central importance: (1) effects of impaired kidney function on drug disposition and response, (2) patient assessment for drug dosing, (3) calculating drug doses for patients with AKI and CKD, and (4) drug removal by intermittent and continuous renal replacement therapies. The breakout group deliberations were reported to the entire group and a consensus-building process led to the clinical practice, research, and regulatory recommendations from the conference attendees, which is the substance of this report. The conference agenda, selected presentations, and abstracts of the meeting are available on the KDIGO website (http://www.kdigo.org/meetings_events/drug_Prescribing_in_KD-Initiative_for_Improved_Dosing.php).

AKI and CKD can affect multiple organ systems and these physiological changes have been associated with profound alterations in the pharmacokinetics (PK) and the pharmacodynamics (PD) of many drugs.[1,2] Clinicians must assess kidney function and consider how the kidney function-associated changes in the disposition of drugs and their active or toxic metabolites will impact the drug therapy needs of individual patients.

The number of patients with AKI and CKD has increased dramatically in the past 10 years.[3,4] Advances in the treatment of disease in general have permitted patients to live longer and many of them develop decreased kidney function over time. Indeed, kidney function decreases with age, and older patients constitute the most rapidly expanding patient group with CKD. The introduction of many novel renal replacement therapies (RRTs) for treating AKI and CKD mandate an understanding of their influence on drug disposition and response. New hemodialysis (HD) membranes and devices, intermittent, automated and continuous peritoneal dialysis, and the development of continuous RRTs necessitate evaluations and in some cases reevaluations of drug transport across biological and artificial membranes.

Pharmacotherapy is now widely utilized to manage chronic conditions by primary care providers, and intensivists are frequently faced with the need to individualize the acute care medication needs while not upsetting the patient's delicate therapeutic balance. CKD patients have poorer health outcomes than patients with normal renal function and the nonoptimization of drug therapy may be one of the contributing factors that could be addressed if more data were available and emphasis was focused on its incorporation into patient care plans.

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